The long-range objective is to explain the connection between abnormal operation of the atrial pacemaker complex (APMC) and atrial flutter (AFL) and fibrillation (AFB). The specific aim of this revised proposal is to determine the mechanisms of spontaneous initiation and termination of atrial reentry tachycardias. Previous work from this laboratory has shown that normal atrial rhythm is controlled by a system of multiple, widely distributed pacemakers. Normally, these distributed pacemaker regions are functionally integrated and either fire synchronously or one site dominates and depolarizes the others as rate changes. Preliminary observations indicate that the APMC plays both pro- and antiarrhythmic roles in the spontaneous initiation and termination of reentrant atrial tachycardias. Evidence indicates that during cholinergic suppression by acetylcholine (ACH) infusion or vagal stimulation, the APMC can depolarize asynchronously, resulting in a series of closely coupled depolarizations similar to an artificial programmable stimulator, spontaneously initiating reentry. This study has been designed to reveal the underlying mechanisms for the asynchronous escape of the APMC and also to define the altered conditions of activation and recovery which comprise the principle intrinsic substrates (of the enhanced vulnerability to asynchronous depolarizations) leading to reentry. In addition, the study will examine the specific interactions between these different factors which are essential to the spontaneous development of AFL and AFB. Studies will be performed in an (in vitro) isolated, perfused right atrial overload that results in either sustained AFL or AFB. Three-dimensional form-fitting electrode molds will be used to record potentials from the irregular epicardial and endocardial surfaces of the atria. Unipolar and bipolar electrograms will be recorded from 250 to 500 sites simultaneously and computer-generated maps of activation and recovery will be produced automatically. Data will be analyzed to determine the response patterns and mechanisms of uncoordinated escape of the atrial pacemakers. Sites of unidirectional conduction block resulting in reentry will be related to fiber orientation by orthogonal pacing at long cycle lengths and by comparison with maps of recovery distribution. Sites of block of reentrant wavefronts will be related to the location and timing of premature escapes of the atrial pacemakers, spatial and temporal changes in recovery, changes in ERP distribution, and paced sites of directionally dependent block. Information derived from experimental canine studies will be linked to mechanisms of spontaneous initiation and termination of AFL and AFB in humans, through studies during cardiac surgery in patients with these arrhythmias. Results of these studies should have important implications for design of surgical, electrical, and pharmacologic approaches to: 1) the control of asynchronous depolarization of the APMC, 2) modification of routes of impulse propagation to prevent unidirectional block, and 3) restoration of homogenous repolarization to the atria.